Controlled release dosage forms for high dose, water soluble and hygroscopic drug substances

ABSTRACT

Controlled release dosage forms are described herein. The controlled release formulations described herein provide prolonged delivery of high dose drugs that are highly water soluble and highly hygroscopic. In specific embodiments, controlled release dosage forms for delivery of a drug selected from GHB and pharmaceutically acceptable salts, hydrates, tautomers, solvates and complexes of GHB. The controlled release dosage forms described herein may incorporate both controlled release and immediate release formulations in a single unit dosage form.

RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application No.61/317,212, filed on Mar. 24, 2010, the contents of which areincorporated herein by reference.

TECHNICAL FIELD

This disclosure relates to controlled release drug compositions.

BACKGROUND

For some drugs, it is difficult to formulate a controlled release dosageform that maintains an effective concentration of the drug over asustained period of time. In particular, drugs that are administered ata high dose, drugs having a low molecular weight, and drugs with highwater solubility make formulation of a controlled release dosage formchallenging. For example, in the context of a controlled release drugformulation produced as a unit dosage form for oral administration,drugs that must be administered at a high dose constrain the amount ofrate controlling excipients that can be used in formulating a drugcomposition that is both capable of sustained delivery of therapeuticdoses of the drug and exhibits a size and shape suited to oraladministration. Low molecular weight and high-solubility drugs may alsoreadily permeate films and matrices that might otherwise be used tocontrol release, and high solubility drugs are not suited to some drugdelivery approaches, particularly where zero-order release kinetics aredesired. An example of a drug that is administered at a high dose, has alow molecular weight, and high water solubility, is gamma-hydroxybutyrate (GHB), particularly the sodium salt of GHB.

Initial interest in the use of GHB as a potential treatment fornarcolepsy arose from observations made during the use of GHB foranesthesia. Unlike traditional hypnotics, GHB induces sleep that closelyresembles normal, physiologic sleep (Mamelak et al., Biol Psych1977:12:273-288). Therefore, early investigators administered GHB topatients suffering from disorders of disturbed sleep, includingnarcolepsy (Broughton et al. in Narcolepsy, NY, NY: SpectrumPublications, Inc. 1976:659-668), where it was found to increase totalnocturnal sleep time, decrease nocturnal awakenings and increase Stage3-4 (slow wave) sleep. Three open-label and two placebo-controlledstudies provided a body of evidence demonstrating that improvements innocturnal sleep were associated with a reduction in cataplexy andimprovements in excessive daytime sleepiness (Broughton et al., Can J.Neurol Sci 1979; 6:1-6, and Broughton et al., Can J. Neurol Sci 1980;7:23-30).

An estimated 6 million Americans suffer the often baffling symptoms offibromyalgia or chronic fatigue syndrome. Patients with fibromyalgia,also referred to as fibromyalgia syndrome, FMS or fibrositis syndrome,report widespread musculoskeletal pain, chronic fatigue, andnon-restorative sleep. These patients show specific regions of localizedtenderness in the absence of demonstrable anatomic or biochemicalpathology, and patients suffering from fibromyalgia typically describelight and/or restless sleep, often reporting that they awaken feelingunrefreshed with pain, stiffness, physical exhaustion, and lethargy.See, H. D. Moldofsky et al., J. Muscoloskel. Pain, 1, 49 (1993). In aseries of studies, Moldofsky's group has shown that aspects of thepatients' sleep pathology are related to their pain and mood symptoms.That is, patients with fibrositis syndrome show an alpha (7.5 to 11 Hz)electroencephalographic (EEG), non-rapid-eye-movement (NREM) sleepanomaly correlated with musculoskeletal pain and altered mood. Moldofskyhas interpreted this alpha EEG NREM sleep anomaly to be an indicator ofan arousal disorder within sleep associated with the subjectiveexperience of non-restorative sleep. See H. D. Moldofsky et al.,Psychosom. Med., 37, 341 (1975).

Fibromyalgia patients frequently report symptoms similar to those ofpatients with post-infectious neuromyasthenia, also referred to aschronic fatigue syndrome (CFS). CFS is a debilitating disordercharacterized by profound tiredness or fatigue. Patients with CFS maybecome exhausted with only light physical exertion. They often mustfunction at a level of activity substantially lower than their capacitybefore the onset of illness. In addition to these key definingcharacteristics, patients generally report various nonspecific symptoms,including weakness, muscle aches and pains, excessive sleep, malaise,fever, sore throat, tender lymph nodes, impaired memory and/or mentalconcentration, insomnia, and depression. CFS can persist for years.Compared with fibromyalgia patients, chronic fatigue patients havesimilarly disordered sleep, localized tenderness, and complaints ofdiffuse pain and fatigue.

Scharf et al. conducted an open-label study to evaluate the effects ofGHB on the sleep patterns and symptoms of non-narcoleptic patients withfibromyalgia (Scharf et al., J Rheumatol 1998; 25: 1986-1990). Elevenpatients with previously confirmed diagnosis of fibromyalgia whoreported at least a 3-month history of widespread musculoskeletal painin all body quadrants and tenderness in a least 5 specific trigger pointsites participated in the study. Results showed that patients reportedsignificant improvements in the subjective assessments of their levelsof pain and fatigue over all 4 weeks of GHB treatment as compared tobaseline, as well as a significant improvement in their estimates ofoverall wellness before and after GHB treatment.

WO 2006/053186 to Frucht describes an open label study of 5 patientswith hyperkinetic movement disorders including ethanol responsivemyoclonus and essential tremor. Sodium oxybate, a sodium salt of GHB,was reported to produce dose-dependent improvements in blinded ratingsof ethanol responsive myoclonus and tremor and was said to be toleratedat doses that provided clinical benefit.

XYREM® sodium oxybate oral solution, the FDA approved treatment forcataplexy and excessive daytime sleepiness associated with narcolepsy,contains 500 mg sodium oxybate/ml water, adjusted to pH=7.5 with malicacid. In man, the plasma half-life of sodium oxybate given orally isabout 45 minutes and doses of 2.25 grams to 4.5 grams induce about 2 to3 hours of sleep (See, L. Borgen et al., J. Clin. Pharmacol., 40, 1053(2000)). Due to the high doses required and very short half-life ofsodium oxybate, optimal clinical effectiveness in narcolepsy typicallyrequires dosing of the drug twice during the night, with administrationtypically recommended at 2.5 to 4 hour intervals. For each dose, ameasured amount of the oral solution is removed from the primarycontainer and transferred to a separate container where it is dilutedwith water before administration. The second dose is prepared at bedtimeand stored for administration during the night.

Liang et al. (published U.S. patent application US 2006/0210630 A1)disclose administration of GHB using an immediate release component anda delayed release component. The delayed release component of theformulations taught in Liang et al., however, function in a pH dependentmanner.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the delivery profile of sodium oxybate controlled releaseformulations as described herein.

FIG. 2 shows the delivery profile of integrated dosage forms asdescribed herein having an immediate release component and a controlledrelease component.

FIG. 3 provides a graph illustrating that the controlled release profileof dosage forms prepared according to the present description can bealtered by altering the coating weight of a functional coating.

FIG. 4 provides a graph further illustrating that the controlled releaseprofile of dosage forms prepared according to the present descriptioncan be altered by altering the coating weight of a functional coating.

FIG. 5 provides a graph illustrating that the controlled release profileof dosage forms prepared according to the present description can bealtered by altering the amount of pore former included within afunctional coating.

FIG. 6 provides a graph further illustrating that the controlled releaseprofile of dosage forms prepared according to the present descriptioncan be altered by altering the amount of pore former included within afunctional coating.

FIG. 7 provides a graph illustrating that the controlled release profileof dosage forms prepared according to the present description can bealtered by varying the molecular weight of a pore former included withina functional coating.

FIG. 8 provides a graph illustrating that suitable controlled releaseprofiles from dosage forms prepared according to the present descriptioncan be achieved even with functional coatings formed using differentgrades of the same base polymer material.

FIG. 9A and FIG. 9B provide graphs illustrating the effects of alcoholon the delivery profile of sustained-release formulations prepared asdescribed herein.

FIG. 10 provides a graph illustrating the controlled release performanceachieved by dosage forms as described herein having functional coatingsprepared from aqueous dispersions of ethylcellulose as the base polymer.

FIG. 11 provides a graph illustrating the controlled release performanceachieved by dosage forms as described herein incorporating calciumoxybate as the drug.

FIG. 12 provides a graph illustrating the plasma concentration of sodiumoxybate over time provided by a sodium oxybate oral solution (TreatmentA) and a sodium oxybate controlled release dosage form as describedherein (Treatment B).

FIG. 13 provides a graph illustrating the plasma concentration of sodiumoxybate over time provided by a sodium oxybate oral solution (TreatmentA) and a sodium oxybate controlled release dosage form as describedherein (Treatment C).

FIG. 14. provides a graph illustrating the plasma concentration ofsodium oxybate over time provided by a sodium oxybate oral solution(Treatment A) and a sodium oxybate controlled release dosage form asdescribed herein dosed at 4 g (Treatment D) and 8 g (Treatment E).

DETAILED DESCRIPTION

Formulations and dosage forms for the controlled release of a drug aredescribed herein. Formulations described herein are suited to thecontrolled release of high dose drugs that are highly water soluble. Inaddition, in certain embodiments, the formulations described hereinprovide controlled release of drugs that are highly hygroscopic, evenwhere such drugs must be administered at relatively high doses. Inparticular embodiments, the controlled release formulations are providedas a unit dosage form, and in one such embodiment, the controlledrelease formulation is provided as a coated tablet.

The formulations and dosage forms of the present invention can alsoinclude an immediate release component. The immediate release componentcan form part of a controlled release (CR) unit dosage form or may be aseparate immediate release composition. Therefore, an immediate release(IR) component may be provided, for example, as a dry powderformulation, an immediate release tablet, an encapsulated formulation,or a liquid solution or suspension. However, the IR component may alsobe formulated as part of a single dosage form that integrates both theIR and CR components. In such an embodiment, the pharmaceuticalformulation may be provided in the form of the coated tablet or capsule.

In specific embodiments, controlled release and immediate releaseformulations can be dosed together to a subject to provide quick onsetof action, followed by maintenance of therapeutic levels of the drugsubstance over a sustained period of time. However, because thecontrolled release component and immediate release component describedherein need not be present in a single dosage form, as it is usedherein, the phrase “dosed together” refers to substantially simultaneousdosing of the controlled release and immediate release components, butnot necessarily administration in the same dosage form. Dosing thecontrolled release and immediate release components together offersincreased convenience, allowing patients to quickly achieve and maintaintherapeutic levels of a drug over a sustained period of time, whilereducing the frequency with which the drug must be dosed. Furthermore,dosing the controlled release and immediate release components togethermay avoid the disadvantages of dosing regimens and formulations thatresult in highly pulsatile plasma concentrations.

An example of a drug that may be used with the controlled release dosageforms described herein is GHB. It should be noted that embodiments ofcontrolled release dosage forms comprising GHB, and other drugs, arepresented herein for purposes of example only and not for purposes oflimitation. The formulations and unit dosage forms provided herein canbe utilized to achieve controlled release of GHB, as well aspharmaceutically acceptable salts, hydrates, tautomers, solvates andcomplexes of GHB. Suitable salts of GHB include the calcium, lithium,potassium, sodium and magnesium salts. The structure of the sodium saltof GHB, sodium oxybate, is given as formula (I):

Methods of making GHB salts are described, for example, in U.S. Pat. No.4,393,236, which is incorporated herein by reference.

Formulating GHB into a unit dosage form presents various challenges, andsuch challenges are magnified in the context of formulating a unitdosage form providing controlled release of GHB. For instance, GHB isvery soluble, generally requires a relatively high dose, has a lowmolecular weight, and exhibits a short circulating half-life onceadministered. Therefore, a controlled release unit dosage form of GHBshould be configured to deliver large doses of drug over a prolongedperiod of time, while being acceptably sized for oral administration.However, controlled release formulations typically require the additionof significant amounts of excipients or rate controlling materials tocontrol the delivery of drug, and the presence and need for suchmaterials often limits the drug loading available for a given controlledrelease technology. Additionally, low molecular weight drugs, such asGHB, typically exhibit high permeability through films and matrices.Even further, high water solubility increases drug mobility and maypreclude the use of some approaches utilized to achieved a controlledrelease dosage form.

Another challenge to achieving a formulation capable of delivering GHBover a sustained period of time is the fact that some forms of GHB, suchas the sodium salt of GHB, sodium oxybate, are extremely hygroscopic. Asused herein, the term “hygroscopic” is used to describe a substance thatreadily absorbs and attracts water from the surrounding environment. Thehygroscopic nature of sodium oxybate presents significant challenges tothe formulation, production, and storage of dosage forms capable ofdelivering sodium oxybate over a sustained period of time. Despite thechallenges noted, formulations and unit dosage forms providingcontrolled release of GHB are described herein.

A. Controlled Release Formulations

As used herein, the term “controlled release” describes a formulation,such as, for example, a unit dosage form, that releases drug over aprolonged period of time. The controlled release compositions describedherein may be provided as a unit dosage form suitable for oraladministration. In each embodiment of the controlled releasecompositions described herein, the drug incorporated in suchcompositions may be selected from GHB and pharmaceutically acceptablesalts, hydrates, tautomers, solvates and complexes of GHB.

In certain embodiments, the controlled release compositions describedherein are formulated as unit dosage forms that deliver therapeuticallyeffective amounts of drug over a period of at least 4 hours. Forexample, controlled release unit dosage forms as described herein may beformulated to deliver therapeutically effective amounts of drug over aperiod selected from about 4 to about 12 hours. In specific embodiments,the controlled release dosage forms described herein delivertherapeutically effective amounts of drug over a period selected fromabout 4, about 5, about 6, about 7, about 8, about 9, about 10 hours,and about 12 hours. In other such embodiments, the controlled releasedosage forms deliver therapeutically effective amounts of drug over aperiod selected from a range of about 4 to about 10 hours, about 5 toabout 10 hours, about 5 to about 12 hours, about 6 to about 10 hours,about 6 to about 12 hours, about 7 to about 10 hours, about 7 to about12 hours, about 8 to about 10 hours, and from about 8 to about 12 hours.In yet other embodiments, the controlled release dosage forms delivertherapeutically effective amounts of drug over a period selected from arange of about 5 to about 9 hours, about 5 to about 8 hours, about 5 toabout 7 hours, and about 6 to about 10 hours, about 6 to about 9 hours,and about 6 to about 8 hours.

The compositions described herein facilitate production of controlledrelease dosage forms that provide a substantially constant drug releaserate. In one embodiment, the controlled release dosage forms may beformulated to deliver not more than approximately 30% of the druginitially contained within the controlled release dosage form in thefirst hour post-administration. When referencing the amount of druginitially contained in the controlled release dosage form or “initialdrug content” of the controlled release dosage form, for purposes of thepresent description, such amount refers to the total amount of drugincluded in the controlled release composition prior to administrationto a patient.

As is detailed herein, the controlled release dosage forms according tothe present description include a controlled release component (alsoreferred to as a controlled release “formulation”) and, optionally, animmediate release component (also referred to as an immediate release“formulation” or an immediate release “coating”). In specificembodiments, the controlled release dosage forms described herein may beformulated to deliver drug to the gastro-intestinal tract at desiredrates of release or release profiles. For example, in some embodiments,controlled release dosage forms as described herein are formulated torelease to the gastro-intestinal tract not more than about 10% to about60% of the drug initially contained within the controlled releasecomponent of the controlled release dosage form during the first twohours post-administration, and not more than about 40% to about 90% ofthe drug initially contained within the controlled release component ofthe controlled release dosage form during the first four hourspost-administration. In other embodiments, controlled release dosageforms as described herein are formulated to release to thegastro-intestinal tract not more not more than about 40% of the druginitially contained within the controlled release component in the firsthour post-administration, not more than about 60% of the drug initiallycontained within the controlled release component during the first twohours post-administration, and not more than about 90% of the druginitially contained within the controlled release component during thefirst four hours post-administration. In still other embodiments, acontrolled release dosage form as described herein may be formulated torelease to the gastro-intestinal tract not more than about 30% of theinitial drug content in the controlled release component in the firsthour post-administration, not more than about 60% of the initial drugcontent in the controlled release component during the first two hourspost-administration, and not more than about 90% of the initial drugcontent of the controlled release component during the first four hourspost-administration. In other embodiments, a controlled release dosageform as described herein may be formulated to release to thegastro-intestinal tract not more than about 50% of the initial drugcontent of the controlled release component during the first hourpost-administration, between about 50 and about 75% of the initial drugcontent of the controlled release component after two hours, and notless than 80% of the initial drug content of the controlled releasecomponent after four hours post administration. In still otherembodiments, a controlled release dosage form as described herein may beformulated release to the gastro-intestinal tract not more than about20% of the initial drug content of the controlled release componentduring the first hour post-administration, between about 5 and about 30%of the initial drug content of the controlled release component aftertwo hours, between about 30% and about 50% of the initial drug contentof the controlled release component after 4 hours, between about 50% andabout 70% of the initial drug content of the controlled releasecomponent after 6 hours, and not less than about 80% of the initial drugcontent of the controlled release component after 10 hours postadministration. In yet other embodiments, a controlled release dosageform as described herein may be formulated to release to thegastro-intestinal tract not more than about 20% of the initial drugcontent of the controlled release component after the first hourpost-administration, between about 20% and about 50% of the initial drugcontent of the controlled release component after 2 hours, between about50% and about 80% of the initial drug content of the controlled releasecomponent after 4 hours, and not less than 85% of the initial drugcontent of the controlled release component after 8 hourspost-administration. The rate and extent of the absorption of GHB variesalong the length of the GI tract with lower amounts absorbed in the moredistal portions (i.e., the ileum and the colon).

Due to the rapid clearance of GHB from the plasma, when GHB isadministered in an immediate release formulation, even large doses ofthe drug (e.g., a dose of between about 2.25 g and 4.5 g) generallyresult in plasma levels below 10 ug/mL within 4 hours of ingestion. Inorder to achieve therapeutic efficacy, therefore, a second, equal, doseis often required within 4 hours after administration of the first dose,and some patients may require administration of a second as soon as 2.5hours after administration of the first dose. In such an instance, inorder to maintain therapeutic efficacy, 4.5 g to 9 g of drug must beadministered to the patient in two separate doses within 2 to 5 hours.This also requires that the second dose be administered during thenight, which requires that the patient be awakened to take the seconddose. The result is that the Cmax/Cmin ratio of GHB over an six hourperiod can be greater than 4 and is often greater than 8. In certainembodiments, for a given dose of GHB, administration of GHB usingcontrolled release dosage forms as described herein can achieve a rapidrise in plasma concentrations of GHB, but with a prolonged duration ofplasma levels above 10 μg/mL. In certain such embodiments, a GHBcontrolled release dosage form as described herein provides a Cmax toCmin ratio of GHB over a prolonged period of time after administrationselected from less than 3 and less than 2. Therefore, in specificembodiments, the controlled release dosage forms described hereinprovided controlled delivery of GHB that results in a Cmax to Cmin ratioof GHB selected from less than 3 and less than 2 over a period of timeselected from up to about 5 hours, up to about 6 hours, up to about 7hours, up to about 8 hours, up to about 9 hours, and up to about 10hours. For example, in particular embodiments, the controlled releasedosage forms described herein provided controlled delivery of GHB thatresults in a Cmax to Cmin ratio of GHB selected from less than 3 over aperiod of time selected from up to about 5 hours, up to about 6 hours,up to about 7 hours, up to about 8 hours, up to about 9 hours, and up toabout 10 hours, while also providing GHB plasma concentrations of atleast 10 μg/mL over a period of time selected from up to about 5 hours,up to about 6 hours, up to about 7 hours, up to about 8 hours, up toabout 9 hours, and up to about 10 hours. In still other embodiments, thecontrolled release dosage forms described herein provided controlleddelivery of GHB that results in a Cmax to Cmin ratio of GHB selectedfrom less than 2 over a period of time selected from up to about 5hours, up to about 6 hours, up to about 7 hours, up to about 8 hours, upto about 9 hours, and up to about 10 hours, while also providing GHBplasma concentrations of at least 10 μg/mL over a period of timeselected from up to about 5 hours, up to about 6 hours, up to about 7hours, up to about 8 hours, up to about 9 hours, and up to about 10hours.

Drug delivery performance provided by the dosage forms described hereincan be evaluated using a standard USP type 2 or USP type 7 dissolutionapparatus set to 37° C.±2° C. under the conditions described, forexample, in the experimental examples provided herein. The dissolutionmedia may be selected from dissolution media known by those of skill inthe art such as at least one of purified water, 0.1N HCl, simulatedintestinal fluid, and others.

In particular embodiments, the controlled release formulations describedherein work to reduce inter patient variability in delivery of GHB. Inparticular, controlled release formulations described herein providetime dependent release of GHB over a sustained period of time. Previousreferences have described targeted release dosage forms of GHB thatfunction in a pH dependent manner. However, due to inter-subjectvariability in gastrointestinal pH conditions, delivery of GHB from suchdosage forms can be inconsistent. Moreover, because relatively highdoses of GHB are typically required for therapeutic effect, unit dosageforms of GHB are also relatively large and may be retained for a periodof time in the stomach, which can lead to intra- and inter-patientvariability in dose delivery of GHB from pH dependent delivery systemsdue to variability in gastric retention time. Further, patients withfibromyalgia have an increased chance of also suffering from irritablebowel syndrome (see, e.g., Fibromyalgia in patients with irritable bowelsyndrome. An association with the severity of the intestinal disorder,Int J Colorectal Dis. 2001 August; 16(4):211-5.) Irritable bowelsyndrome is also associated with delayed gastric emptying and variablegastric emptying (see, e.g., Dyspepsia and its overlap with irritablebowel syndrome, Curr Gastroenterol Rep. 2006 August; 8(4):266-72.)Therefore many patients with fibromyalgia and suffering from irritablebowel syndrome may experience more variability in gastric transit orprolonged gastric transit. By operating in a time dependent manner onceplaced in an aqueous environment, controlled release formulationsdescribed herein offer consistent GHB delivery characteristics andreduce the likelihood of undesirable intra- and inter-patientinconsistencies in dose delivery that may result from variances ingastric retention time that can occur between different patients anddifferent patient populations.

Controlled release formulations described herein may be formulated tocompletely release a drug within a desired time interval. As has beenreported, the bioavailability of GHB decreases in the lower GI, withbioavailability decreasing the lower the drug is delivered in the GI(See, e.g., U.S. Patent Publication No. US2006/0210630). Therefore, incertain embodiments, the controlled release dosage forms are providedthat deliver substantially all the GHB contained therein over asustained period of time that is long enough to increase patientconvenience, yet short enough to reduce dosing of GHB in the lower GI.In specific embodiments, controlled release GHB dosage forms areprovided that deliver approximately 90% or more of the GHB containedwithin the controlled release formulation within about 4 to about 10hours of administration. For example, dosage forms for the controlledrelease of GHB as described herein may be formulated to deliverapproximately 90% or more of the drug included within the controlledrelease formulation within about 4, 5, 6, 7, 8, 9, 10, or 12 hours ofadministration. In one such embodiment, a dosage form for the sustaineddelivery of GHB according to the present description is formulated todeliver more than 90% of the GHB included within the controlled releaseformulation within 12 hours post-administration. Such embodiments serveto not only provide controlled release of GHB, but they also work todeliver GHB where bioavailability is highest, which can also provideincreased dose consistency.

The controlled release dosage forms described herein may comprise arelatively high concentration of drug that can, in some instances, harma patient if the formulation releases the drug at a rate that is fasterthan the intended sustained rate. This rapid release of the drug issometimes referred to as “dose dumping.” To avoid this potential danger,certain embodiments of the controlled release dosage forms describedherein may comprise formulations that are resistant to dose dumping.Some users may intentionally attempt to increase the drug release rateof the controlled release dosage form using alcohol (e.g., potentialabusers may take the controlled release dosage form prior to,simultaneously with, or after consuming an alcoholic beverage or,alternatively, may seek to extract the drug from the controlled releasedosage form by placing the dosage form in solution containing alcohol).Other users may take the dosage form with alcohol, not necessarily in amanner considered abuse of the drug or alcohol, but without regard forthe potential risks of dose dumping or contraindication of the twosubstances. In one embodiment, a controlled release dosage form asdisclosed herein may include a coating composition that is resistant toalcohol or that does not dissolve substantially faster in alcohol. Inone such embodiment, the controlled release dosage form may comprise thedrug sodium oxybate and include a coating composition includingethylcellulose that is resistant to dose dumping in alcohol. In anotherembodiment, the controlled release dosage form may include a coatingcomposition that is resistant to dose dumping after administration. Forexample, the controlled release dosage form may include a coatingcomposition that is resistant to dose dumping in the GI tract afterbeing exposed to gastric fluid and intestinal fluid.

In certain embodiments, the controlled release formulations describedherein are provided as a coated tablet composition having a controlledrelease core coated by a functional overcoat. The composition of thecontrolled release core provided in such embodiments facilitates highdrug loading, thereby, rendering the coated tablet suitable forformulation and sustained delivery of drugs administered at high doses.The functional overcoat works to control delivery of drug from thecontrolled release core and maintain the structural integrity of thedosage form over time. In addition to the controlled release core andfunctional overcoat, the coated tablet composition as described hereinmay further include a moisture barrier or cosmetic coating disposed overthe functional overcoat.

I. Controlled Release Component

Where the controlled release formulations described herein areformulated as a coated tablet having a controlled release core (CRcore), the CR core includes at least one drug substance to be deliveredfrom the controlled release dosage form. The drug included in the CRcore may be selected from GHB and pharmaceutically acceptable salts,hydrates, tautomers, solvates and complexes of GHB. Examples of suitablesalts of GHB include the calcium, lithium, potassium, sodium andmagnesium salts. The CR core is formulated and configured to be suitablefor oral administration. In one embodiment, coated tablets as describedherein may be administered to provide a dose of GHB or apharmaceutically acceptable salt, hydrate, tautomer, solvate or complexof GHB in a range of about 500 mg to about 12 g of drug in one or moretablets. In particular embodiments, a CR core included in a controlledrelease dosage form according to the present description may include anamount of drug selected from about 100 mg to about 2,000 mg. In somesuch embodiments, the amount of drug included in the CR core may beselected from up to about 250 mg, 400 mg, 500 mg, 600 mg, 700 mg, 750mg, 800 mg, 900 mg, 1,000 mg, 1,100 mg, 1,200 mg, 1,400 mg, 1,500 mg,1,600 mg, 1,700 mg, 1,800 mg, 1,900 mg, and 2,000 mg. In certain suchembodiments, the amount of drug included in a CR core as describedherein may range from about 500 mg to about 2,000 mg, such as, forexample, about 500 mg to 1,000 mg, about 600 mg to 1,000 mg, about 600mg to 900 mg, about 600 mg to 800 mg, about 700 mg to 1,000 mg, about700 mg to 900 mg and about 700 mg to 850 mg. In other such embodiments,the amount of drug included in a CR core as described herein may rangefrom about 700 mg to about 2,000 mg, such as, for example, about 700 mgto 1,500 mg, about 700 mg to 1,400 mg, about 700 mg to 1,300 mg, about700 mg to 1,200 mg, about 700 mg to 1,100 mg, about 700 mg to 1,000 mg,about 700 mg to 900 mg, and about 700 mg to 850 mg.

In one embodiment, the controlled release dosage form comprises a CRcore wherein the relative amount drug in the CR core is at least 90% orgreater by weight. In another embodiment, the relative amount of drug inthe CR core ranges from between about 90% and 98%, about 91% and 98%,about 92% and 98%, about 93% and 98%, about 94% and 98%, about 95% and98%, about 96% and 98%, and between about 97% and 98% by weight of theCR core. In yet another embodiment, the relative amount of drug in a CRcore may be present at an amount selected from about 90%, 91%, 92%, 93%,94%, 95%, 96%, 97%, and 98% by weight of the CR core. In certain suchembodiments, the amount of drug in the CR core may range from about 94to 98%, 94 to 97%, 94 to 96%, 95 to 98%, 95 to 97%, and 95 to 96.5% byweight of the CR core.

In one embodiment, the controlled release dosage form comprises a CRcore that includes drug substance in combination with one or moreexcipients, such as binders, fillers, diluents, disintegrants,colorants, buffering agents, coatings, surfactants, wetting agents,lubricants, glidants, or other suitable excipients. In one embodiment, aCR core as disclosed herein can include one or more binders that areknown for use in tablet formulations. In one such embodiment, a CR coremay include at least one binder selected from hydroxypropyl cellulose(HPC), ethylcellulose, hydroxypropyl methylcellulose (HPMC),hydroxyethyl cellulose, povidone, copovidone, pregelatinized starch,dextrin, gelatin, maltodextrin, starch, zein, acacia, alginic acid,carbomers (cross-linked polyacrylates), polymethacrylates,carboxymethylcellulose sodium, guar gum, hydrogenated vegetable oil(type 1), methylcellulose, magnesium aluminum silicate, and sodiumalginate. In specific embodiments, the CR core included in a controlledrelease dosage form as disclosed herein may comprise binder levelsranging from approximately 1% to 10% by weight. For example, the CR coremay include a binder in an amount selected from about 1%, 1.5%, 2%,2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 6%, 7%, 8%, 9%, and 10% by weight. Incertain such embodiments, the amount of binder included in the CR coremay range from about 1 to 2%, 1 to 3%, 1 to 4%, 1 to 5%, 1 to 6%, 1 to7%, 1 to 8%, 1 to 9% and 1 to 10% by weight.

The CR core may include one or more lubricants to improve desiredprocessing characteristics. In one embodiment, the CR core may includeone or more lubricants selected from at least one of magnesium stearate,stearic acid, calcium stearate, hydrogenated castor oil, hydrogenatedvegetable oil, light mineral oil, magnesium stearate, mineral oil,polyethylene glycol, sodium benzoate, sodium stearyl fumarate, and zincstearate. In another embodiment, one or more lubricants may be added tothe CR core in a range of about 0.5% to 5% by weight. In particularembodiments, a CR core as disclosed herein may comprise a lubricant in arange of about 0.5% to 2% by weight, about 1% to 2% by weight, about 1%to 3% by weight, about 2% to 3% by weight, and about 2% to 4% by weight.In one such embodiment, one or more lubricants may be present in the CRcore in an amount selected from about 0.5%, 1%, 1.5%, 2%, 2.5%, 3%,3.5%, 4%, 4.5%, and 5% by weight. Still lower lubricant levels may beachieved with use of a “puffer” system during tabletting, which applieslubricant directly to the punch and die surfaces rather than throughoutthe formulation.

The CR core may also include one or more surfactants. In certainembodiments, the CR core may include a tableted composition that maycomprise one or more surfactants selected from, for example, ionic andnon-ionic surfactants. In one such embodiment, CR core may include atleast one anionic surfactant, including docusate sodium (dioctylsulfosuccinate sodium salt) and sodium lauryl sulfate. In yet anotherembodiment, the CR core may include at least one non-ionic surfactantselected from including polyoxyethyelene alkyl ethers, polyoxyethylenestearates, poloxamers, polysorbate, sorbitan esters, and glycerylmonooleate. In specific embodiments, one or more surfactants included ina CR core as disclosed herein may be present, for example, in an amountof up to about 3.0% by weight of the CR core. For example, in certainembodiments, the CR core may include one or more surfactants present ina range selected from about 0.01% to 3%, about 0.01% to 2%, about 0.01%to 1%, about 0.5% to 3%, about 0.5% to 2%, and about 0.5% to 1% byweight of the CR core.

The CR core included in controlled release dosage form as disclosedherein may also include fillers or compression aids selected from atleast one of lactose, calcium carbonate, calcium sulfate, compressiblesugars, dextrates, dextrin, dextrose, kaolin, magnesium carbonate,magnesium oxide, maltodextrin, mannitol, microcrystalline cellulose,powdered cellulose, and sucrose. In another embodiment, a CR core may beprepared by blending a drug and other excipients together, and theforming the blend into a tablet, caplet, pill, or other dosage formaccording to methods known by those of skill in the art. In certainembodiments, a controlled release formulation as described herein maycomprise a solid oral dosage form of any desired shape and sizeincluding round, oval, oblong cylindrical, or triangular. In one suchembodiment, the surfaces of the CR core may be flat, round, concave, orconvex.

The CR core composition included in a controlled release formulationprovided as a coated tablet dosage form as described herein may bemanufactured using standard techniques, such as wet granulation, rollercompaction, fluid bed granulation, and direct compression followed bycompression on a conventional rotary tablet press as described inRemington, 20^(th) edition, Chapter 45 (Oral Solid Dosage Forms).

II. Functional Coating Composition

Where the controlled release formulations as described herein areprovided as a coated tablet composition, the CR core is coated with afunctional coating. The coating composition works to preserve theintegrity of the unit dosage form post administration and serves tofacilitate controlled release of drug from the CR core. In certainembodiments, the coating composition is formulated to facilitatecontrolled release of a drug selected from GHB and pharmaceuticallyacceptable salts, hydrates, tautomers, solvates and complexes of GHB. Inone such embodiment, the coating composition is sufficiently robust topreserve the integrity of the coated tablet pre- andpost-administration, yet is subject to disintegration or crushing as itpasses through a patient's gastrointestinal tract and after all orsubstantially all the drug substance contained within the controlledrelease formulation has been delivered. Such a feature reduces the riskthat bezoars formed from intact dosage form shells will form or bemaintained within the GI tract of a patient, which may be of particularconcern where the drug to be delivered must be administered at highdoses using multiple unit dosage forms.

In one embodiment, a functional coating composition as disclosed hereinmay control, at least in part, the rate of release of the drug to bedelivered from the CR core into the gastrointestinal tract. In oneembodiment, the functional coating composition provides a functionalcoat that partly or fully covers the CR core included in the controlledrelease dosage form. In one embodiment, the functional coatingcomposition as disclosed herein may include a polymer or blends ofcompatible polymers that are water soluble or that are water insolubleand selected to exhibit desired permeability characteristics. In oneembodiment, the functional coating composition has a permeability thatmay be adjusted according the solubility of the drug used in the CRcore. In one such embodiment, the functional coating composition maycomprise one or more water insoluble polymers that may swell but do notsubstantially dissolve in the GI tract. For example, in particularembodiments, a functional coating composition as disclosed herein maycomprise a rate-limiting film that includes at least one ofethylcellulose, cellulose acetate, such as CA-398. In other embodiments,the functional coating may include combinations of ethylcellulose withammonio methacrylate copolymers, such as EUDRAGIT RS, EUDRAGIT RL, andcombinations thereof. Suitable ethylcellulose materials are readilycommercially available, and include, for example, ETHOCEL ethylcellulosepolymers. Where ethylcellulose is used to form the functional coating,the physical characteristics of the coating composition and residualshell may be modified by adjusting the molecular weight of theethylcellulose. For example, different grades of ethylcellulose,including, but not limited to, 4 cP, 7 cP, 10 cP, and 20 cP grades, maybe used to achieve a coating composition having desired physicalcharacteristics.

A functional coating composition as disclosed herein may include one ormore base polymer and at least one pore-former. In one embodiment, thebase polymer content may range from about 50% to about 80% by weight ofthe coating composition. In certain embodiments, the base polymer may bepresent in an amount ranging from about 50% to 75%, about 55% to 75%,about 60% to 75%, and about 65% to 75% by weight of the coatingcomposition. In one such embodiment, the base polymer may be present inan amount selected from about 50%, 55%, 60%, 65%, 70%, 75%, and 80% byweight of the coating composition. In cases where a filler material isused (e.g., insoluble, non film-forming material such as magnesiumstearate, talc, or fumed silica), these limits apply to the compositionof the remaining non-filler components in the film.

The permeability of the base polymer included in a functional coating asdescribed herein may be modified by including a pore former in the basepolymer. In one such embodiment, the functional coating compositionincluding the pore former may be obtained by combining the pore formerwith the base polymer material in solution according to conventionaltechniques. A pore former as disclosed herein may include at least onepolymeric pore former, such as hydroxyalkyl cellulose, hydroxypropylmethylcellulose, hydroxypropyl cellulose, polyethylene glycols,polyvinyl alcohol, povidone, copovidone, and poloxamers, such as 188 or407. In one embodiment, a pore former as disclosed herein may include atleast one small-molecule pore former, such as a water soluble sugar ororganic acid, including, for example, citric acid or sorbitol. In onesuch embodiment, a small-molecule pore former may be water solubleactive agent, such as a pharmaceutically acceptable salt of GHB. In yetanother embodiment, the pore former may comprise a polymer that expandsin the presence of the drug included in the CR core, wherein expansionof the pore former may cause an increase in permeability of thefunctional coating composition. For example, in some embodiments, thefunctional coating composition may comprise a pore former that thatexpands or swells in the presence of sodium oxybate. In one suchembodiment, the pore former includes a suitable carbomer.

Where used in the functional coating composition, a pore former or apore-forming agent can be selected to modify the permeability of thecoating composition provided over the CR core. For example, thepermeability of the functional coating composition may be increased byincluding one or more pore formers or pore-forming agents in the coatingcomposition. In one embodiment, the pore formers disclosed herein may besoluble in water. In one such embodiment, when a CR dosage formcomprising a functional coating composition with at least one poreformer is swallowed by a patient and contacted with gastric fluid, thewater-soluble pore formers may dissolve and form pores or channels inthe coating through which the drug is released. It is possible to use anenteric component as part or all of the pore former in the coatingcomposition. Examples of such materials that may be used as a poreformer in the context of the present description include celluloseacetate phthalate, methacrylic acid-methyl methacrylate copolymers, andpolyvinyl acetate phthalate. However, incorporating enteric componentsin the film may result in delivery characteristics that exhibit somelevel of sensitivity to gastric and intestinal transit times.

Where included, the amount and nature of the pore former included in thefunctional coating composition can be adjusted to obtain desired releaserate characteristics for a given drug substance. In one embodiment, thefunctional coating composition may include an amount of pore former thatranges from about 20% to about 50% by weight of the coating composition.For example, the pore former may be present in an amount ranging fromabout 20% to 45%, about 25% to 45%, about 30% to 45%, and about 35% to45% by weight of the functional coating composition. In one suchembodiment, the pore former may be present in an amount selected fromabout 20%, 25%, 30%, 35%, 40%, 45%, and 50% by weight of the functionalcoating composition.

The functional coating composition as disclosed herein may also compriseone or more plasticizers. In certain embodiments, the functional coatingcomposition may include a plasticizer such as triethyl citrate ordibutyl sebacate. In one such embodiment, a plasticizer may be presentin the functional coating composition in an amount ranging from about 5%to 15% by weight relative to the base polymer. In certain embodiments,the functional coating composition may include a plasticizer in anamount selected from about 5%, 8%, 10%, 12%, and 15% by weight relativeto the base polymer.

The functional coating composition as disclosed herein may also includean anti-tack agent. For example, certain embodiments of the functionalcoating composition may include an anti-tack agent selected from one ormore of talc, glyceryl monostearate, and magnesium stearate. Many of theanti-tack agents are also suitable fillers. Addition of fillers,especially magnesium stearate, is one way to make the film more brittleand the dosage form more prone to crushing as it transits through theGI. Depending on forces encountered in the GI, varying the filler levelin the film may allow one to adjust the duration, or extent of drugdelivered, at which breach of the film and abrupt release of remainingcontents occurs.

The functional coating composition as disclosed herein may be applied toa CR core at a weight that facilitates a suitable combination ofsustained drug release and dosage form structural integrity. In certainembodiments, the functional coating composition may be applied at aweight of about 10 to about 100 mg. In particular embodiments, forexample, the functional coating may be applied at a weight selected fromabout 20 to 60 mg, about 20 to 50 mg, about 20 to 40 mg, about 20 to 30mg, about 30 to 60 mg, about 30 to 50 mg, about 30 to 40 mg, about 40 to60 mg, about 40 to 50 mg, and about 50 to 60 mg. These ranges are usefulfor oval tablets of about 500 mg to about 1000 mg in weight.Alternatively, for a given tablet size or weights, the functionalcoating composition as disclosed herein may be applied at between about2.5% and 7.5% of the tablet weight. For example, in one such embodiment,where the tablet is a 2,000 mg oval tablet, a functional coatingcomposition may be applied at a weight ranging from about 50 mg to about150 mg.

In addition to adjusting the amount or nature of the pore formerincluded in the functional coating composition, the release rate of drugprovided by the controlled release dosage form disclosed herein may beadjusted by modifying the thickness or weight of the functional coatingcomposition. For example, a more rapid release rate will generally beachieved as the amount of a given pore former included in the functionalcoating composition is increased or the thickness or weight of thecoating composition applied over the CR core is decreased. Conversely, aslower or more controlled release may be achieved, generally, asrelatively less of a given pore former is included in the functionalcoating composition or the thickness or weight of the coatingcomposition applied to the CR core is increased. Additionally, incertain embodiments, the release rate of drug from the CR core may beadjusted by modifying the water content of the functional coatingcomposition. For example, increasing the water content of the functionalcoating composition may increase the release rate of drug the CR core.

The functional coating compositions as disclosed herein may be appliedto a CR core according to conventional coating methods and techniques.In one embodiment, the functional coating composition as disclosedherein may be applied using a conventional perforated pan coater. Inanother embodiment, the functional coating composition may be appliedusing an aqueous pan-coating process. In one such embodiment, the use ofan aqueous pan-coating process may include the use of a latexdispersion. For example, a latex dispersion such as SURELEASE may beused for an ethylcellulose pan-coating process. In another example, alatex dispersion such as EUDRAGIT RS 30 D may be used in a pan-coatingprocess for ammonio-methacrylates. In yet another embodiment, thefunctional coating composition may be applied using a solvent-basedpan-coating process. In one such embodiment, a solvent-based pan-coatingprocess may include the use of an alcohol solvent, such as ethanol. Forexample, an alcohol-solvent based pan-coating process may utilize a 95%ethanol and 5% water (w/w) solvent.

In one embodiment, the functional coating compositions as describedherein may be applied using a fluid bed coating process such as aWurster fluid bed film coating process. In another embodiment, thefunctional coating composition may be applied using a compressioncoating process. In yet another embodiment, the functional coatingcomposition may be applied using a phase inversion process. In certainembodiments, the functional coating composition as disclosed herein maybe applied over a suitable subcoating.

III. Moisture Barrier/Cosmetic Coatings

When a controlled release formulation or dosage form is provided as acoated tablet, in some embodiments, it may be coated with a moisturebarrier or a moisture-resistant coating composition. For example, acontrolled release dosage form as disclosed herein comprising GHB as thedrug substance may include a moisture barrier. In another example, amoisture barrier may be particularly useful where sodium oxybate is usedas the drug substance. In one embodiment, the moisture barrier may be apolyvinyl alcohol-based coating, such as OPADRY AMB (Colorcon Inc.,Harleysville, Pa.). In another embodiment, the moisture barrier may be ahydroxypropyl methylcellulose (HPMC)/wax-based coating, such as AQUARIUSMG (Ashland Aqualon, Wilmington, Del.). In yet another embodiment, themoisture barrier may be a HPMC/stearic acid-based coating. The moisturebarrier as disclosed herein, in some embodiments, may be formed using areverse enteric material, such as EUDRAGIT E, and may be coated fromalcohol or alcohol/water solutions or from an aqueous latex dispersion.In embodiments where the controlled release dosage form is provided as atablet of about 500 mg-1000 mg in weight, for example, the moisturebarrier coating may be applied at a weight selected from about 10 mg toabout 60 mg/tablet and about 25 mg to about 50 mg/tablet. In general, aminimum weight is needed to ensure complete coverage of the tablet inlight of imperfections in the tablet surface, and a maximum weight isdetermined by practical considerations, such as coating time, or by theneed for better moisture protection.

As will be readily appreciated, the controlled release dosage form canbe further provided with a cosmetic top coat. In one embodiment, atop-coat may be applied to an existing coating composition such as amoisture barrier. In certain embodiments, a cosmetic top-coat mayinclude at least one of HPMC and copovidone. For example, when thecontrolled release dosage form includes a coated tablet comprisingsodium oxybate as the drug, a top-coat including HPMC, such as forexample an HPMC material selected from one or more of HPMC E3, E5, orE15, may be applied over a moisture barrier to improve the effectivenessof the moisture barrier by reducing any seepage of sodium oxybate andwater from the surface of the coated tablet.

B. Immediate Release Formulations

The controlled release formulations described herein can be dosedtogether with an immediate release (IR) formulation. In one embodiment,the IR formulation may be provided as a separate formulation or dosageform that may be dosed together with a dosage form provided by acontrolled release dosage form as described herein. The IR formulationmay be provided in any suitable form, such as a dry powder formulation,a tablet or capsule unit dosage form, or a liquid formulation such as asolution or suspension formulation. As used herein, “immediate release”refers to a drug formulation that releases more than about 95% of thedrug contained therein within a period of less than one hour afteradministration. In particular embodiments, the IR component of thecompositions described herein release more than about 95% of the drugcontained therein within a period selected from less than 45 minutes,less than 30 minutes, and less than 15 minutes post-administration. Inother embodiments, the IR component of the compositions described hereinrelease more than about 80% of the drug contained therein within aperiod selected from less than 45 minutes, less than 30 minutes, andless than 15 minutes post-administration.

In certain embodiments, the IR formulation is provided as an immediaterelease component of a controlled release dosage form as describedherein. In one such embodiment, the IR component is provided as acoating over a controlled release component or formulation as describedherein. A unit dosage form that integrates both controlled release andimmediate release components can increase the convenience and accuracywith which a drug such as GHB is dosed to patients by providing a unitdosage form that not only provides quick onset of action, but alsosustained delivery of GHB to the patient over a prolonged period oftime. Furthermore, where the drug to be delivered is selected from GHBand pharmaceutically acceptable salts, hydrates, tautomers, solvates andcomplexes of GHB, dosing controlled release and immediate releaseformulations together may avoid the disadvantages of the current GHBdosing regimens, which can result in highly pulsatile plasmaconcentrations.

I. Immediate Release Component

When the immediate release formulation is provided as an integrated IRcomponent of a controlled release dosage form, the amount of drugincluded in the IR component may range from about 10% to 50% by weightof the total drug included in the integrated dosage form. As usedherein, “integrated dosage form” refers to a single unit dosage formthat includes both immediate release and controlled release componentsas described herein. For example, where the drug to be delivered fromthe immediate release and controlled release formulations incorporatedinto an integrated dosage form is selected from GHB and pharmaceuticallyacceptable salts, hydrates, tautomers, solvates and complexes of GHB insome embodiments, the drug included in the IR component may compriseabout 10% to about 50% by weight of the total drug included in the unitdosage form. In one such embodiment, the drug included in the IRcomponent of an integrated dosage form may comprise about 10%, 15%, 20%,25%, 30%, 35%, 40%, 45%, or 50% by weight of the total drug included inthe unit dosage form. For example, an integrated dosage form asdescribed herein may contain 1000 mg sodium oxybate, wherein 100 mg to500 mg sodium oxybate (10% to 50% by weight) is contained within anddelivered from the IR component and 500 mg to 900 mg sodium oxybate (50%to 90% by weight) is contained within and delivered from the CRcomponent.

Where the IR component is provided as a coating over a controlledrelease dosage form, in certain embodiments, the drug included in the IRcomponent may account for between about 75% and 98% by weight of the IRformulation. In the context of describing an IR component provided overa controlled release dosage form as described or disclosed herein, thecontrolled release dosage forms referred to include the controlledrelease formulations described herein, including, in specificembodiments, CR cores coated with a functional coating as describedherein. Again, the drug included in such an embodiment may be selectedfrom GHB and pharmaceutically acceptable salts, hydrates, tautomers,solvates and complexes of GHB. In certain embodiments, the IR componentmay comprise sodium oxybate in an amount of selected from a range ofbetween about 75% and 98%, between about 80% and 98%, between about 85%and 98%, between about 90% and 98%, and between about 95% and 98% byweight.

An IR component formed as a coating over a controlled release dosageform as disclosed herein may be applied as a tableted overcoat accordingto conventional tablet coating and binding methods. Alternatively, an IRcomponent formed as a coating over a controlled release dosage form asdisclosed herein may be applied as a film coating, such as, for example,from a solution containing a suitable amount of drug and film former. Inone such embodiment, wherein sodium oxybate is the drug included in theIR component, the coating forming the IR component may be coated over acontrolled release dosage form from a coating solution that utilizes analcohol and water solvent. For example, a suitable immediate releasecoating may be formed using a 20% solution of sodium oxybate in a60%/40% (w/w) alcohol/water solution that contains a suitablefilm-former.

Where the IR component is provided as a film coat and includes one ormore film-formers, suitable film formers may be selected from, forexample, copovidone, hydroxypropyl cellulose, HPMC, and hydroxymethylcellulose materials. An IR component containing sodium oxybate as thedrug can be applied as a suspension or as a solution by adjusting thewater content of the coating mixture. For a suspension, little or nowater is added to the alcohol, and the example film formers should besuitable. To prepare a solution, however, the water content of thesolvent is increased, for example to 40%, and a smaller set of filmformers would be suitable due to the precipitation of most common filmformers in the presence of sodium oxybate solution. Hypromellose is oneof several potential film formers that is suitable. It is furtherpossible, with more difficulty, to apply the sodium oxybate from anaqueous solution; however, the same limitations on film former applies,and processing is complicated by the hygroscopic nature of the drug. Inone embodiment, the IR component useful for use in a controlled releasedosage form as described herein includes 91% sodium oxybate and 9%hypromellose (HPMC E-15) that is applied from a solution containing 20%sodium oxybate and 2% HPMC E-15 in a 60/40 w/w ethanol/water solvent.

Where the IR component of an integrated dosage form is provided as acoating over the controlled release dosage form, the coating forming theIR component may further include one or more of an anti-tack agent and aplasticizer to facilitate processing and to improve film properties.Furthermore, addition of one or more surfactants, such as sodium laurylsulfate, may improve the dissolution of IR coatings that containhydrophobic components (such as anti-tack agents or water-insoluble filmformers).

In embodiments where the IR component is provided as a coating over acontrolled release formulation as described herein, the IR component maybe positioned directly over the functional coating of the controlledrelease formulation. Where desired or necessary based on the drug to bedelivered from the IR component and controlled release formulationincluded in such an integrated dosage form, the outer surface of the IRcomponent may then be coated with a moisture barrier layer. For example,where the drug delivered by the integrated dosage form is highlyhygroscopic, such as, for example, sodium oxybate, a moisture barrierlayer over the immediate release coating forming the IR component may beprovided.

The formulation and structure of integrated dosage forms as describedherein can be adjusted to provide a combination of immediate release andcontrolled release performance that suits a particular dosing need. Inparticular, the formulation and structure of integrated dosage forms asdescribed herein can be adjusted to provide any combination of theimmediate release and controlled release performance characteristicsdescribed herein. In particular embodiments, for example, the drugdelivered from an integrated dosage form as described herein is selectedfrom GHB and pharmaceutically acceptable salts, hydrates, tautomers,solvates and complexes of GHB, and the integrated dosage form sustainsdelivery of GHB over a period of from about 4 to about 10 hours. In onesuch embodiment, the IR component of the integrated dosage form providesrapid onset of action, releasing more than about 90% of the drugcontained therein within a period of time selected from less than onehour, less than 45 minutes, less than 30 minutes and less than 15minutes after administration, while the controlled release compositionincluded in the integrated dosage begins to deliver drug as the IRcomponent is released and continues to deliver drug for a sustainedperiod of between about 4 and about 10 hours. In another suchembodiment, the IR component of the integrated dosage form providesrapid onset of action, releasing more than about 90% of the drugcontained therein within a period of time selected from less than onehour, less than 45 minutes, less than 30 minutes and less than 15minutes after administration, while the controlled release compositionincluded in the integrated dosage begins to deliver drug after the IRcomponent is released and continues to deliver drug for a sustainedperiod of between about 4 and about 10 hours.

Moreover, the ratio of drug release from the IR component and CRcomponent can be adjusted as needed to facilitate a desired dosingregimen or achieve targeted dosing. A dosage form as described hereinthat integrates both IR and CR components may be formulated to deliveras much as 2,000 mg of a desired drug, such as GHB or a pharmaceuticallyacceptable salt, hydrate, tautomer, solvates or complex of GHB. Inparticular embodiments, the total amount of drug contained within anintegrated IR/CR dosage form according to the present description may bebetween about 500 mg and about 1,400 mg. For example, in certain suchembodiments, the total amount of drug may be selected from between about500 mg and 1,400 mg, about 500 mg and 1,200 mg, about 500 mg and 1,100mg, about 600 mg and 1,200 mg, about 600 mg and 1,100 mg, about 600 mgand 1,000 mg, about 600 mg and 950 mg, about 600 mg and 850 mg, about600 mg and 750 mg, about 750 mg and 1,200 mg, about 750 mg and 1,100 mg,about 750 mg and 1,000 mg, about 750 mg and 950 mg, and about 750 mg and850 mg. In an integrated IR/CR dosage form, the relative amounts of drugdelivered from the IR component and CR components may be adjusted asdesired as well. In particular embodiments, the ratio of drug releasedfrom the IR component to drug released from the CR component is fromabout 1:2 to about 1:4. In certain embodiments, such ratio is selectedfrom about 1:2, 1:2.5, 1:3, 1:3.5 and 1:4.

In particular embodiments, the integrated dosage form may be formulatedsuch that the controlled release formulation begins release of drugsubstantially simultaneously with delivery of the drug from the IRcomponent. Alternatively, the integrated dosage form may be formulatedsuch that controlled release formulation exhibits a start-up time lag.In one such embodiment, for example, the integrated dosage form maybeformulated and configured such that start-up of delivery of drug fromthe controlled release composition occurs after delivery of drug fromthe IR component is substantially complete. Where a start-up lag time isdesired, an enteric coating may be applied over the controlled releasecomponent (e.g., over a functional coating), but such a coating wouldnecessarily limit the start-up lag to gastric residence and itsassociated variability. Use of enteric pore-formers would also impart astart-up lag, and such an embodiment would be more sensitive to foodeffects and gastric motility. Where a less pH-sensitive start-up lagtime is desired, the delay may be accomplished or adjusted by the use ofone or more coatings and films, including the functional coatingprovided over a CR core and, where utilized, the moisture barrier orcosmetic overcoats. In particular, start-up lag time as disclosed hereinmay be adjusted by modifying the formulation, thickness, and/or weightof the functional coating provided over the CR core, the moisturebarrier layer or one or more non-functional or cosmetic overcoats.

EXAMPLES Example 1—Controlled Release Core

A granulation used to form CR cores as described herein was manufacturedin a 25 L high shear granulator according to the formula in Table 1A.Klucel EXF was divided into two equal portions; half of the Klucel EXFwas dissolved in the ethanol, and half was dry blended with sodiumoxybate. The material was initially granulated with 10% w/w ethanol andthen titrated with another 3.5% w/w ethanol solution to achieve desiredgranule growth. A suitable wet mass was obtained at a total ethanolconcentration of 13.5% w/w. The wet granules were divided into two sublots and then each sub lot was dried in a 5-liter Niro fluid bed dryer.The dried granules were combined and milled through a COMIL equippedwith a 14 mesh screen. Granulation parameters and particle sizedistribution are shown in Tables 1B and 1C, respectively.

The granulation was then combined with 2% magnesium stearate lubricant,and tablets were compressed on a 16-station press fitted withchrome-plated 0.325″×0.705″ modified oval tooling. The average tablethardness was 10.7 kiloponds.

TABLE 1A Controlled Release Core Tablet Formulation Ingredient(s) % w/wmg/tablet 1 Sodium Oxybate 96.0 750.0 2 Hydroxypropyl cellulose, NF(Klucel EXF) 2.0 15.6 3 Ethanol, USP (200 proof)* 13.5 4 MagnesiumStearate, NF 2.0 15.6 TOTAL 100.0 781.2 *Granulation solvent, removedduring drying step

TABLE 1B Granulation Parameters WET GRANULATION GRANULATION SOLUTION 250ADDITION RATE (G/MIN) TOTAL GRANULATION TIME 7 MINUTES (INCLUDINGSOLUTION ADDITION AND WET MASSING TIME) IMPELLER SPEED (RPM) 300 CHOPPERSPEED (RPM) 1800  DRYING SUBLOT 1 SUBLOT 2 DRYING INLET 70 70TEMPERATURE (° C.) TOTAL DRYING TIME 17 18 (MIN) EXHAUST TEMPERATURE 4748 AT END OF DRYING (° C.) LOD (% WT LOSS) 0.84 0.92

TABLE 1C Screen Analysis of Milled Granulation Screen size Opening sizeWt Retained US Std mesh microns (%) 20 850 2.1 40 420 10.4 60 250 19.880 180 25.0 120 125 22.9 200 75 12.5 Pan <45 7.3

Example 2—Functional Coating

Tablets from Example 1 were coated with a solution prepared according tothe formulation in Table 2A. The ethylcellulose was first added to a95/5 w/w mixture of ethanol and water and stirred until dissolved. Next,the hydroxypropyl cellulose and dibutyl sebacate were added and stirreduntil completely dissolved. 4.7 kg of tablets from Example 1 were thencharged to an 8″ pan Driam tablet coater and coated with the solution to5.1 wt % gain (40 mg/tablet). The tablets were then dried for 5 minutesin the coater, and then finally cooled in the pan to an exhausttemperature below 30° C.

The dissolution profile was measured in de-ionized water using USPApparatus 2 set to 37° C.±2° C. with paddles at 50 rpm. Samples wereanalyzed by HPLC. As shown in FIG. 1, the coated tablets exhibitedcontrolled release with duration of approximately 6 hours. The dosageform released 12% of its contents after 1 hour, 34% after 2 hours, 71%after 4 hours, 93% after 6 hours, and 99% after 8 hours.

TABLE 2A Formulation of Sodium Oxybate Sustained-Release Tablets % ofcoat % w/w of mg/ Ingredient(s) solids tablet tablet 5 Sodium Oxybatetablet core 95.13 781.25 6 Hydroxypropyl cellulose, 37.0 1.80 14.80 NF(Klucel EF) 7 Dibutyl sebacate 5.0 0.24 2.00 8 Ethylcellulose, NF(Ethocel 58.0 2.82 23.20 Standard Premium 10) 9 Ethanol, USP (200proof)* 10 Purified water* TOTAL 100.0 100.00 821.25 *Coating solvent,removed during processing

TABLE 2A Coating Parameters for Driam 8″ Pan Coater CR COATING AVERAGERANGE INLET TEMPERATURE (° C.) 46 42-55 EXHAUST TEMPERATURE (° C.) 4341-46 INLET AIRFLOW (PASCAL) >300 >300 ATOMIZATION PRESSURE (BAR) 2 2.0SPRAY RATE (G/MIN) 35 32-37 PAN SPEED (RPM) 6 5-7

Example 3—Immediate-Release Overcoat

A solution of 20% sodium oxybate as active and 2.0% hypromellose E-15(HPMC E-15) as film-former was prepared in 60/40 (w/w) ethanol/water.The coating solution was manufactured by first dissolving the HPMC E15in water, then adding the ethanol and sodium oxybate. 3 kg of 750-mgstrength sustained-release tablets from Example 2 were charged to aDriam tablet coater equipped with an 8″ pan and preheated to 40° C. Theentire coating solution was applied according to the parameters listedin Table 3A. The tablet weight gain was monitored every 5 minutes, andthe coating was stopped when the entire solution was sprayed (thetheoretical weight gain is 33.5%). The tablets were dried for 15minutes; the tablets did not lose any weight during the 15 minute dryingtime, and so it was assumed that the drying was complete. The tabletswere then cooled in the pan to an exhaust temperature of <30° C.

Analysis by HPLC revealed an overall potency of 961 mg, and thus a drugovercoat potency of 211 mg. Dissolution testing using USP Apparatus 2set to 37° C.±2° C. with paddles at 50 rpm, shown in FIG. 2,demonstrates substantially the entire immediate-release overcoat isdissolved in 15 minutes and that controlled release is maintained forapproximately 6 hours thereafter. Higher amounts of drug can be appliedto the immediate release overcoat by using higher amounts of coatingsolution and extending the coating time accordingly.

TABLE 3A Parameters for Immediate-Release Overcoating with 8″ DriamCoater DRUG OVER-COATING AVERAGE RANGE INLET TEMPERATURE (° C.) 59 55-63EXHAUST TEMPERATURE (° C.) 51 50-53 PRODUCT TEMPERATURE (° C.) 43 41-49INLET AIRFLOW (PASCAL) >300 >300 ATOMIZATION PRESSURE (BAR) 2 2 SPRAYRATE (G/MIN) 16 14-17 PAN SPEED (RPM) 8 7-8 TOTAL RUN TIME (HRS) 4 HRS47 MIN (COATING) 15 MIN (DRYING)

The following examples illustrate aspects of the sustained-releasecoating formulation with several evaluations using tablets from Example1.

Example 4—Effect of Membrane Weight with Poloxamer as Pore Former inFunctional Coating

One means of controlling dissolution is by adjustment of the coatingthickness, or amount of film applied to each tablet. This wasillustrated with a film consisting of 33% poloxamer 188 (P188) and 67%ethylcellulose 10 cPs (EC-10). The coating solution was prepared bydissolving 3.59 grams of EC-10 and 1.77 grams of P188 in a mixture of 80grams denatured alcohol (“alcohol”) and 4 grams de-ionized water.(Denatured alcohol, S-L-X manufactured by W. M. Barr, is approximately a50/50 w/w blend of methanol and ethanol.)

Twelve tablets from Example 1 were coated in a Caleva Mini-coater/Drier2 under parameters listed in Table 4A. Periodically, the tablets wereremoved and weighed to determine film weight. Three tablets were removedat times corresponding to 21 mg, 30 mg, 40 mg, and finally 60 mg weightgain.

The dissolution profiles were measured with USP Apparatus 7 (VankelBio-dis) set to 37° C.±2° C. and using a dipping rate of 30/minute,tablets fixed in plastic holders and intervals corresponding to 0.5 h, 1h, 1.5 h, 2 h, 3 h, 4 h, 5 h, 6 h, 7 h, 8 h, and 14 h (each interval is50 ml volume). The tubes were analyzed by conductivity, and results arecalculated as percent of total amount. The results demonstrate thatcontrolled release is achieved with membrane weights ranging from atleast 21-60 mg/tablet, and that duration of delivery increases as themembrane weight increases.

TABLE 4A Standard Parameters for Sustained-Release Coating in CalevaMini-Coater/Drier 2 Parameter Setting Batch size 3-12 Tablets Inlettemperature 40° C. Air flow setting 70-85% Solution flow rate 18 ml/hrAgitator setting 32 Atomization pressure 0.5 bar Gun position Adjustedto achieve desired deposition

Example 5—Effect of Membrane Weight with Hydroxypropyl Cellulose as PoreFormer in Functional Coating

Following procedures of Example 4, 12 tablets from Example 1 were coatedwith a film consisting of 36.5% HPC-EF, 5.0% dibutyl sebacate (DBS), and58.5% EC-10 (all percentages by weight) coated from a solutionconsisting of 7% solids in 95/5 alcohol/water. The results shown in FIG.4 demonstrate that controlled release over a relevant time period isachieved with membrane weights ranging from at least 21-60 mg/tablet,and that duration of delivery increases as the membrane weightincreases.

Example 6—Effect of Poloxamer Level in Functional Coating

In addition to adjustment of membrane weight, another useful means ofcontrolling release rate or duration is by adjustment of the pore-formercontent of the formulation. Following procedures of Example 4, twoadditional solutions consisting of (a) 25% P188 by weight/75% EC-10 byweight and (b) 40% P188 by weight/60% EC-10 by weight were prepared as7% (w/w) solutions in 95/5 alcohol/water. In each of the two separatecoatings, four tablets from Example 1 were coated to 41 mg. Thedissolution profiles are shown in FIG. 5, along with that of the 40 mgset of Example 4 for comparison. The results demonstrate that poloxamerlevel can be adjusted at least over the range of 25%-40% by weight,while still providing controlled release of the drug.

Example 7—Effect of Hydroxypropyl Cellulose Level in Functional Coating

In a fashion similar to Example 6, the effect of HPC level in thefunctional coating was evaluated over the range of 30%-50% by weight.Three separate coating solutions were prepared with 30%, 40%, and 50%HPC-EF; 5% DBS; and the balance EC-10. All solutions were prepared with7% total components in 95/5 alcohol/water. In each coating, 4 tabletsfrom Example 1 were coated to 40-41 mg/tablet weight gain. Thedissolution profiles shown in FIG. 6 demonstrate controlled release ofthe drug was achieved with HPC levels of at least 30-50% by weight.

Example 8—Effect of Hydroxypropyl Cellulose Molecular Weight when usedin Functional Coating

Hydroxypropyl cellulose is supplied in several molecular weight grades,many of which may be suitable for use as pore-formers in ethylcellulosefilms. Two such grades (Klucel “EF” and “JF”, supplied by Ashland)corresponding to 80,000 daltons and 140,000 daltons were evaluated withother components fixed. Following procedures of Example 4, solutionswere prepared with 40% HPC, 5% DBS, and 55% EC-10 (all percentages byweight) using 7% total components in 95/5 alcohol/water. In eachcoating, 4 tablets from Example 1 were coated to 40-41 mg/tablet weightgain. The results shown in FIG. 7 demonstrate a modest effect ofmolecular weight and that the two grades tested provide for acceptablerelease profiles.

Example 9—Effect of Ethylcellulose Molecular Weight or Viscosity

Another consideration is the molecular weight, or viscosity, ofethylcellulose. Two grades were evaluated, corresponding to 4 cPs and 10cPs viscosity for a 5% solution. Following procedures of Example 4, twosolutions were prepared corresponding to 58.5 wt % ethylcellulose (EC-4or EC-10), 36.5 wt % HPC-EF, and 5.0 wt % DBS having 7% w/w totalcomponents in 95/5 alcohol/water. Tablets from Example 1 were coated to40 mg/tablet weight gain, and dissolution profiles are shown as FIG. 8.The results indicate both grades of ethylcellulose provide foracceptable profiles, and suggest that other ethylcellulose grades (suchas 20 cPs) may also be acceptable.

Example 10—Demonstration of Alcohol Ruggedness of Controlled ReleaseSodium Oxybate Tablets

Co-administration of sustained-release dosage forms with alcoholicbeverages is a relevant concern, as ethanol is known to dissolve certainrate-controlling components that would not otherwise be dissolved. Insome dosage forms, this may lead to dose-dumping. As ethanol is rapidlyabsorbed in the stomach, a relevant test involves dissolution of thedosage form in vodka (40% ethanol nominal) for 2 hours (representinggastric retention time), followed by normal dissolution in de-ionizedwater.

This test was performed on sustained-release tablets from Example 9(36.5 wt % HPC EF, 5 wt % DBS, 58.5 wt % EC-4). The analysis of sodiumoxybate by conductivity was corrected for the different response invodka vs. de-ionized water. The results shown in FIG. 9A indicate thatdissolution is slower in Vodka, and that no dose-dumping occurred.

Likewise, a similar test was performed on sustained-release tablets witha film comprised of 33 wt % P188 and 67 wt % EC-10. Those results, shownin FIG. 9B, also indicate slower release in vodka and no dose-dumping.

Example 11—Aqueous Coating of Controlled Release Film

Due to the hygroscopic nature of sodium oxybate, coating therate-controlling film from an alcoholic solution is desirable. However,use of ethylcellulose aqueous dispersions is attractive forenvironmental and cost considerations. A film consisting of 30 wt % HPCEF and 70 wt % Surelease (aqueous ethylcellulose dispersion) wasdeposited on tablets from Example 1 as follows. First, 1.37 grams of HPCEF was dissolved in 22.6 grams de-ionized water. This was then pouredinto 32.5 grams of Surelease E-7-19040-clear while stirring. Eighttablets were coated in the Caleva Mini-coater/Drier 2 with flow rate of15 ml/hr and 58° C. inlet temperature. Samples removed at 24 mg and 40mg were then tested for dissolution, with no post-coating heattreatment. The results are shown in FIG. 10.

Example 12—Calcium Oxybate Controlled Release

A controlled release dosage form for delivery of calcium oxybate wasprepared by generally following procedures of Example 1 found in U.S.Pat. No. 4,393,296 (Klosa, Production of Nonhygroscopic Salts of4-Hydroxybutyric Acid). The isolated calcium oxybate was milled to passthrough a 16-mesh screen. For this study, a small sample comprising 9.3grams of calcium oxybate was blended with 0.19 grams of sodium stearylfumarate (Pruv, JRS Pharma, Rosenberg, Germany). 800 mg aliquots of this98% calcium oxybate and 2% sodium stearyl fumarate were then directlycompressed into tablets using 0.325″×0.705″ modified oval tooling and aCarver press with 1-ton applied force. Following procedures of Example4, nine tablets were coated with a film having 33% poloxamer 188 and 67%EC-10 from a solution of 7% w/w solids in 95/5 alcohol/water. Twotablets were removed at each intermediate coating weight correspondingto 20 mg, 32 mg, 41 mg, and finally at 60 mg. The dissolution profilesare shown as FIG. 11. These results using calcium oxybate follow thegeneral behavior of sodium oxybate demonstrated in Example 4.

Example 13—Clinical Evaluation of Controlled Release Dosage Forms

An open-ended, randomized, crossover study was conducted to evaluatecontrolled release dosage forms as described herein. The controlledrelease dosage forms were formulated to deliver sodium oxybate and werecompared to a sodium oxybate oral solution (commercially available asXyrem® (sodium oxybate) oral solution). The study was conducted inhealthy male and female volunteers.

Four different sodium oxybate formulations were administered topatients. The first, designated herein as Treatment A, was the sodiumoxybate oral solution containing 375 mg/ml sodium oxybate. Treatments Bthrough E, as designated herein, involved administration of threecontrolled release dosage forms (Treatments B through D), with one ofthe controlled release dosage forms being used to administer twodifferent doses of sodium oxybate (Treatments D and E). The controlledrelease dosage forms administered as Treatment B included 750 mg sodiumoxybate per dosage form and were produced with a CR core and functionalovercoat as described in Example 1 and Example 2, the controlled releasedosage forms administered as Treatment C included 750 mg sodium oxybateper dosage form and were produced as described in Example 1 and Example4, and the controlled release dosage forms administered as Treatments Dand E included 1,000 mg sodium oxybate per dosage form and were producedwith a CR core (750 mg sodium oxybate), functional overcoat, and IRovercoat (250 mg sodium oxybate) as described in Examples 1 through 3.

Patients were divided into two groups. The first group receivedTreatment A, Treatment B, and Treatment C over the course of theclinical study, with a washout period between each treatment. TreatmentA was administered to each patient as two 3 g doses given four hoursapart (one dose at time zero and the second dose four hours later), fora total dose of 6 g sodium oxybate. Treatments B and C were administeredto each patient only at time zero, with each treatment beingadministered as 8 tablets, providing a total dose of 6 g sodium oxybate.Blood samples from each patient were taken at various intervals andanalyzed by LC/MS for total sodium oxybate content in the plasma. Atotal of 29 patients received Treatment A, a total of 19 patientsreceived Treatment B, and a total of 19 patients received Treatment C.The mean plasma concentration of sodium oxybate over time achieved byeach of the treatments is shown in FIG. 12 (Treatment A and Treatment B)and FIG. 13 (Treatment A and Treatment C), and a summary ofpharmacokinetic parameters provided by Treatments A through C areprovided in Table 5.

TABLE 5 Summary of PK Parameters for Treatments A, B, C T_(1/2) CmaxAUClast AUCinf λ_z (1/hr) (hr) Tmax (hr) ^(a) (ug/ml) (hr * ug/ml) (hr *ug/ml) Treatment A N 29 29 29 29 29 29 Mean 1.22 0.60 4.50 (0.5, 4.75)130.79 350.84 351.20 SD 0.27 0.13 31.52 116.74 116.74 CV % 21.93 22.6124.10 33.27 33.24 Mean 1.19 0.58 127.37 333.33 333.72 Treatment B N 1818 19 19 19 18 Mean 0.62 1.22 2.00 (1.50, 5.00) 41.78 188.23 196.25 SD0.16 0.40 18.40 103.60 102.50 CV % 26.44 32.58 44.03 55.04 52.23 Mean0.59 1.17 38.46 163.80 173.33 Treatment C N 19 19 19 19 19 19 Mean 0.740.99 2.50 (1.00, 5.00) 50.49 221.64 222.60 SD 0.16 0.23 15.83 106.85106.80 CV % 22.25 22.93 31.35 48.21 47.98 Mean 0.72 0.96 48.10 200.08201.12

The second group was administered Treatment A, Treatment D, andTreatment E during over the course of the clinical study, with a washoutperiod between each treatment. Again, Treatment A was administered toeach patient as two 3 g doses given four hours apart (one dose at timezero and the second dose four hours later), for a total dose of 6 gsodium oxybate. Treatments D and E were administered to each patientonly at time zero. Patients receiving Treatment D were administered 4tablets at time zero, providing a total dose of 4 g sodium oxybate, andpatients receiving Treatment E were administered 8 tablets at time zero,providing a total dose of 8 g sodium oxybate. Blood samples from eachpatient were taken at various intervals and analyzed by LC/MS for totalsodium oxybate content in the plasma. A total of 30 patients receivedTreatment A, and a total of 30 patients received Treatments D and E. Themean plasma concentration of sodium oxybate over time achieved by eachof the treatments is shown in FIG. 14, and a summary of pharmacokineticparameters provided by Treatments A through C are provided in Table 6.

TABLE 6 Summary of PK Parameters for Treatments A, D, E T_(1/2) CmaxAUClast AUCinf λ_z (1/hr) (hr) Tmax (hr) ^(a) (ug/ml) (hr * ug/ml) (hr *ug/ml) Treatment A N 30 30 30 30 30 30 Mean 1.08 0.71 4.50 (0.50, 5.50)114.59 301.28 301.59 SD 0.31 0.27 27.91 100.85 100.87 CV % 29.00 37.9024.36 33.47 33.45 Mean 1.03 0.67 111.20 285.47 285.79 Treatment D N 3030 30 30 30 30 Mean 0.46 1.63 0.75 (0.50, 2.50) 25.10 64.44 65.58 SD0.14 0.47 7.33 20.36 20.26 CV % 30.27 29.00 29.20 31.60 30.90 Mean 0.441.56 24.01 61.31 62.55 Treatment E N 30 30 30 30 30 30 Mean 0.59 1.361.00 (0.50, 5.00) 59.52 242.30 243.80 SD 0.20 0.64 17.72 117.15 116.79CV % 34.57 46.91 29.77 48.35 47.91 Mean 0.55 1.25 56.89 216.33 218.12^(a) Tmax is summarized as median (min, max).

It will be obvious to those having skill in the art that many changesmay be made to the details of the above-described embodiments withoutdeparting from the underlying principles of the invention. The scope ofthe present invention should, therefore, be determined only by thefollowing claims.

1-108. (canceled)
 109. A method for treating cataplexy or excessivedaytime sleepiness associated with narcolepsy in a patient in needthereof comprising delivering to the patient a formulation comprisingimmediate release and sustained release portions, each portioncomprising at least one pharmaceutically active ingredient selected fromgamma-hydroxybutyrate and pharmaceutically acceptable salts ofgamma-hydroxybutyrate, wherein: a. the sustained release portioncomprises a functional coating and a core, wherein the functionalcoating is deposited over the core, wherein the core comprises at leastone pharmaceutically active ingredient selected fromgamma-hydroxybutyrate and pharmaceutically acceptable salts ofgamma-hydroxybutyrate wherein the functional coating comprises one ormore methacrylic acid-methyl methacrylate co-polymers that are fromabout 20% to about 50% by weight of the functional coating; thesustained release portion comprises about 500 mg to 12 g of at least onepharmaceutically active ingredient selected from gamma-hydroxybutyrateand pharmaceutically acceptable salts of gamma-hydroxybutyrate; and thesustained release portion releases greater than about 40% of itsgamma-hydroxybutyrate by about 4 to about 6 hours when tested in adissolution apparatus 2 in deionized water at a temperature of 37° C.and a paddle speed of 50 rpm; b. the immediate release portion comprisesabout 75% and about 98% by weight of at least one pharmaceuticallyactive ingredient selected from gamma-hydroxybutyrate andpharmaceutically acceptable salts of gamma-hydroxybutyrate, and theamount of gamma-hydroxybutyrate and pharmaceutically acceptable salts ofgamma-hydroxybutyrate in the immediate release portion is about 10% to50% by weight of the total gamma-hydroxybutyrate and pharmaceuticallyacceptable salts of gamma-hydroxybutyrate in the formulation; c. theformulation releases at least about 30% of its gamma-hydroxybutyrate byone hour when tested in a dissolution apparatus 2 in deionized water ata temperature of 37° C. and a paddle speed of 50 rpm; and d. theformulation releases greater than about 90% of its gamma-hydroxybutyrateby 8 hours when tested in a dissolution apparatus 2 in deionized waterat a temperature of 37° C. and a paddle speed of 50 rpm.
 110. The methodof claim 109 wherein the formulation releases greater than about 90% ofits gamma-hydroxybutyrate by 7 hours when tested in a dissolutionapparatus 2 when tested in a dissolution apparatus 2 in deionized waterat a temperature of 37° C. and a paddle speed of 50 rpm.
 111. The methodof claim 109 wherein the formulation releases greater than about 90% ofits gamma-hydroxybutyrate by 6 hours when tested in a dissolutionapparatus 2 when tested in a dissolution apparatus 2 in deionized waterat a temperature of 37° C. and a paddle speed of 50 rpm.
 112. The methodof claim 109 wherein the sustained release portion releases about 60% toabout 90% of its gamma-hydroxybutyrate by about 6 hours when tested in adissolution apparatus 2 in deionized water at a temperature of 37° C.and a paddle speed of 50 rpm.
 113. The method of claim 109 wherein thesustained release portion comprises hydrogenated vegetable oil,hydrogenated castor oil, or mixtures thereof.
 114. The method of claim109 wherein the formulation comprises a calcium, lithium, potassium,sodium or magnesium salt of gamma-hydroxybutyrate or mixtures thereof.115. The method of claim 114 wherein the formulation comprises a sodiumsalt of gamma-hydroxybutyrate.
 116. The method of claim 109 wherein theimmediate release portion comprises 50% by weight of the totalgamma-hydroxybutyrate.
 118. The method of claim 109, wherein the one ormore methacrylic acid-methyl methacrylate co-polymers comprise fromabout 30% to about 45% by weight of the functional coating.
 119. Themethod of claim 109 wherein the sustained release portion releases about10% or less of its gamma-hydroxybutyrate by about 1 hour when tested ina dissolution apparatus 2 in deionized water at a temperature of 37° C.and a paddle speed of 50 rpm.
 120. A method for treating cataplexy orexcessive daytime sleepiness associated with narcolepsy in a patient inneed thereof comprising delivering to the patient a formulation of atleast one pharmaceutically active ingredient selected fromgamma-hydroxybutyrate and pharmaceutically acceptable salts ofgamma-hydroxybutyrate, comprising immediate release and a solidsustained release portions: a. wherein the immediate release portioncomprises about 55 mg to 12 g of at least one pharmaceutically activeingredient selected from gamma-hydroxybutyrate and pharmaceuticallyacceptable salts of gamma-hydroxybutyrate; b. wherein the sustainedrelease portion comprises from about 500 mg to 12 g of at least onepharmaceutically active ingredient selected from gamma-hydroxybutyrateand pharmaceutically acceptable salts of gamma-hydroxybutyrate and afunctional coating deposited over a core comprising the at least onepharmaceutically active ingredient, wherein the functional coatingcomprises one or more methacrylic acid-methyl methacrylate co-polymersthat are from about 20% to about 50% by weight of the functionalcoating; and the sustained release portion releases greater than about40% of its gamma-hydroxybutyrate by about 4 to 6 hours when tested in adissolution apparatus 2 in deionized water at a temperature of 37° C.and a paddle speed of 50 rpm; c. the formulation releases at least about30% of its gamma-hydroxybutyrate or salt thereof by one hour when testedin a dissolution apparatus 2 in deionized water at a temperature of 37°C. and a paddle speed of 50 rpm; and d. the formulation releases greaterthan about 90% of its gamma-hydroxybutyrate by 8 hours when tested in adissolution apparatus 2 in deionized water at a temperature of 37° C.and a paddle speed of 50 rpm.
 121. A method for treating cataplexy orexcessive daytime sleepiness associated with narcolepsy in a patient inneed thereof comprising delivering to the patient a formulationcomprising immediate release and sustained release portions, eachportion comprising at least one pharmaceutically active ingredientselected from gamma-hydroxybutyrate and pharmaceutically acceptablesalts of gamma-hydroxybutyrate, wherein: a. the sustained releaseportion comprises a functional coating and a core, wherein thefunctional coating is deposited over the core, wherein the corecomprises at least one pharmaceutically active ingredient selected fromgamma-hydroxybutyrate and pharmaceutically acceptable salts ofgamma-hydroxybutyrate; wherein the functional coating comprises one ormore methacrylic acid-methyl methacrylate co-polymers that are fromabout 20% to about 50% by weight of the functional coating; thesustained release portion comprises about 500 mg to 12 g of at least onepharmaceutically active ingredient selected from gamma-hydroxybutyrateand pharmaceutically acceptable salts of gamma-hydroxybutyrate; and thesustained release portion releases greater than about 40% of itsgamma-hydroxybutyrate by about 4 to about 6 hours when tested in adissolution apparatus 2 in deionized water at a temperature of 37° C.and a paddle speed of 50 rpm; b. the immediate release portion furthercomprises one or more pharmaceutically acceptable excipients selectedfrom the group consisting of copovidone, plasacryl, hydroxypropylcellulose, hydroxypropyl methylcellulose and hydroxymethyl cellulose,and the amount of gamma-hydroxybutyrate and pharmaceutically acceptablesalts of gamma-hydroxybutyrate in the immediate release portion is about10% to 50% by weight of total gamma-hydroxybutyrate and pharmaceuticallyacceptable salts of gamma-hydroxybutyrate in the formulation; c. theformulation releases at least about 30% of its gamma-hydroxybutyrate byone hour when tested in a dissolution apparatus 2 in deionized water ata temperature of 37° C. and a paddle speed of 50 rpm; and d. theformulation releases greater than about 90% of its gamma-hydroxybutyrateby 8 hours when tested in a dissolution apparatus 2 in deionized waterat a temperature of 37° C. and a paddle speed of 50 rpm.
 122. The methodof claim 121, wherein the formulation releases greater than about 90% ofits gamma-hydroxybutyrate by 7 hours when tested in a dissolutionapparatus 2 in deionized water at a temperature of 37° C. and a paddlespeed of 50 rpm.
 123. The method of claim 121, wherein the formulationreleases greater than about 90% of its gamma-hydroxybutyrate by 6 hourswhen tested in a dissolution apparatus 2 in deionized water at atemperature of 37° C. and a paddle speed of 50 rpm.
 124. The method ofclaim 121, wherein the sustained release portion releases about 60% toabout 90% of its gamma-hydroxybutyrate by about 6 hours when tested in adissolution apparatus 2 in deionized water at a temperature of 37° C.and a paddle speed of 50 rpm.
 125. The method of claim 121, wherein thesustained release portion comprises hydrogenated vegetable oil,hydrogenated castor oil, or mixtures thereof.
 126. The method of claim121, wherein the formulation comprises a calcium, lithium, potassium,sodium or magnesium salt of gamma-hydroxybutyrate or mixtures thereof.127. The method of claim 126, wherein the formulation comprises a sodiumsalt of gamma-hydroxybutyrate.
 128. The method of claim 121, wherein theimmediate release portion comprises 50% by weight of the totalgamma-hydroxybutyrate.
 129. The method of claim 121, wherein the one ormore methacrylic acid-methyl methacrylate co-polymers comprise fromabout 30% to about 45% by weight of the functional coating.
 130. Themethod of claim 121, wherein the one or more pharmaceutically acceptableexcipients comprise hydroxypropyl cellulose.
 131. The method of claim121, wherein the one or more pharmaceutically acceptable excipientscomprise hydroxypropyl methylcellulose.
 132. The method of claim 121,wherein the one or more pharmaceutically acceptable excipients are about10% by weight of the immediate release portion.
 133. The method of claim121, wherein the sustained release portion releases about 10% or less ofits gamma-hydroxybutyrate by about 1 hour when tested in a dissolutionapparatus 2 in deionized water at a temperature of 37° C. and a paddlespeed of 50 rpm.
 134. A method for treating cataplexy or excessivedaytime sleepiness associated with narcolepsy in a patient in needthereof comprising delivering to the patient a formulation of at leastone pharmaceutically active ingredient selected fromgamma-hydroxybutyrate and pharmaceutically acceptable salts ofgamma-hydroxybutyrate, comprising immediate release and a solidsustained release portions: a. wherein the immediate release portioncomprises about 55 mg to 12 g of at least one pharmaceutically activeingredient selected from gamma-hydroxybutyrate and pharmaceuticallyacceptable salts of gamma-hydroxybutyrate and about 10% by weight of oneor more pharmaceutically acceptable excipients selected from the groupconsisting of copovidone, plasacryl, hydroxypropyl cellulose,hydroxypropyl methylcellulose and hydroxymethyl cellulose; b. whereinthe sustained release portion comprises from about 500 mg to 12 g of atleast one pharmaceutically active ingredient selected fromgamma-hydroxybutyrate and pharmaceutically acceptable salts ofgamma-hydroxybutyrate and a functional coating deposited over a corecomprising the at least one pharmaceutically active ingredient, whereinthe functional coating comprises one or more methacrylic acid-methylmethacrylate co-polymers that are from about 20% to about 50% by weightof the functional coating; and the sustained release portion releasesgreater than about 40% of its gamma-hydroxybutyrate by about 4 to 6hours when tested in a dissolution apparatus 2 in deionized water at atemperature of 37° C. and a paddle speed of 50 rpm; c. the formulationreleases at least about 30% of its gamma-hydroxybutyrate or salt thereofby one hour when tested in a dissolution apparatus 2 in deionized waterat a temperature of 37° C. and a paddle speed of 50 rpm; and d. theformulation releases greater than about 90% of its gamma-hydroxybutyrateby 8 hours when tested in a dissolution apparatus 2 in deionized waterat a temperature of 37° C. and a paddle speed of 50 rpm.
 135. The methodof claim 134, wherein the one or more pharmaceutically acceptableexcipients comprise hydroxypropyl methylcellulose.
 136. The method ofclaim 134, wherein the one or more pharmaceutically acceptableexcipients comprise hydroxypropyl cellulose.